We have developed what we believe to be the first characterization of a specific lesion in the membranes of lymphocytes and fibroblasts derived from individuals with Down's Syndrome. This lesion can be demonstrated by the careful observation of various physical-chemical properties of fluorescent phospholipid probes implanted in the plasma membrane. Compounds of this type have already been synthesized in our laboratory, but several others are being synthesized, each for a specific purpose with respect to understanding membrane structure. Characteristic differences between normal and Down's syndrome cells are observed by monitoring both the temperature dependence and rotational mobility of our probes incorporated into the plasma membranes of these cells. As will be described later in detail, considerable preliminary data has already been generated, including a comparison between normal, trisomy-21 and other abnormal cells. With new fluorescence instrumentation developed in the past two years, we propose to extend our analysis from the steady state method heretofore used to nanosecond and sub-nanosecond fluorescence lifetime and polarization measurements. Although these methods have never (to our knowledge) been used in such studies, it seems logical to us to employ these biophysical techniques, which are capable of indicating minute differences in membrane characteristics, in the analysis of disorders where the biochemical bases are so diffuse and poorly understood.